This renewal application represents a multidisciplinary approach to study mechanisms that regulate metabolic activities and differentiating events in the developing central nervous system (CNS). It is vital to determine these basic aspects in the developing CNS since changes in any of these elements may result in deficits that ultimately lead to various forms of mental retardation. During the past funding cycle our studies have provided cogent evidence to support many of our original hypotheses related to metabolic trafficking and energy metabolism, including results that showed marked alteration in amino acid composition of the interstitial fluid and brains oxidative metabolism in response to leucine and alpha-ketoisocaproate, compartmentation of glutamine and glutamate oxidation in the brain; that the formation of lactate by brain cells from glutamate was a function of the concentration of glutamate and alpha- ketoisocaproate, and that the structural protein spectrin may anchor the Na+/K+ATPase activity in the neuronal membrane. The proposal will focus on regulation and compartmentation of oxidative metabolism in brain and the effect of branched chain amino acids on this process, transport of large neutral amino acids by individual types of brain cells, the interrelation between monocarboxylic acids and amino acids in trafficking between different types of brain cells, the role of specific membrane components in transport and energy metabolism in the CNS, the regulation of enzymes involved in synthesis of arginine and nitric oxide, and the role of kynurenic acid in neuroprotective mechanisms in the developing brain. The results of this integrated multidisciplinary approach utilizing cultures of specific human and rat brain cells, nuclear magnetic resonance, microdialysis of the living brain, brain slices, and laser confocal scanning microscopy to address an unified series of questions will enhance our understanding of the complex CNS matrix and the varied metabolic and differentiating events which when altered give rise to many types of mental retardation. These studies will also provide guidance for the clinical management of infants with developmental disabilities.